Process Validation

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Process Validation

• Case Study - Inspection of a Process

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Objectives

• Overview of Regulation
• FDA 483 Trends specific to Process Validation
• Inspection Process

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Process Validation

• 820.3(z) Validation
• Means confirmation by examination and provision
  of objective evidence that the particular
  requirements for a specific intended use can be
  consistently fulfilled

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Process Validation

• 820.3(z)(1) Process Validation
• Means establishing by objective evidence that a
  process consistently produces a result or product
  meeting its predetermined specifications

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Process Validation

• 820.75(a)
• Where the results of a process cannot be fully
  verified by subsequent inspection and test, the
  process shall be validated with a high degree of
  assurance and approved according to established
  procedures

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When is 820.75(a) Applicable?

• The initial validation of a process
• Destructive testing is required to demonstrate
  the manufacturing process produced product
  meeting specifications
• All quality attributes of a device cannot be
  analyzed by routine testing

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Question

• If you have a process validation in place, does
  this mean you cannot be cited for an observation
  under 820.75(a)?

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Process Validation

• 820.75(b)
• Each manufacturer shall establish and maintain
  procedures for monitoring and control of process
  parameters for validated processes to ensure that
  the specified requirements continue to be met

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Process Validation

• 820.75(b)(2)
• For validated processes, the monitoring and
  control methods and data, the date performed,
  and, where appropriate, the individual(s)
  performing the process or the major equipment
  used shall be documented

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When is 820.75(b) Applicable?

• Applies to the performance of a process after the
  process has been validated
• Routine monitoring
• Manufacturer uses multiple manufacturing lines or
  equipment to produce the product

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Question

• Must a manufacturer continuously monitor a
  validated process?

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Preamble Comment 145

• Monitoring can be accomplished at a determined
  interval and frequency
• The interval and frequency should be periodically
  evaluated for adequacy, especially during any
  evaluation or revalidation that occurs in
  accordance with the requirements under 820.75(c)

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Process Validation

• 820.75(c)
• When changes or process deviations occur, the
  manufacturer shall review and evaluate the
  process and perform revalidation where appropriate

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When is 820.75(c) Applicable?

• Process changes
• Equipment changes
• Product (design) changes
• Process deviations

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Question

• Do the requirements under 820.70 (Production and
  process controls) apply to a validated process?

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Preamble Comment 125

• 820.70(b), Production and process changes,
  addresses the requirement for production and
  process changes to be verified or where
  appropriate validated according to 820.75
• The agency notes that whenever changes may
  influence a validated process, the process must
  be revalidated as described in 820.75

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Preamble Comment 4

• The regulation is less prescriptive and gives the
  manufacturer the flexibility to determine the
  controls that are necessary commensurate with
  risk
• The burden is on the manufacturer, however, to
  describe the types and degree of controls and how
  those controls were decided upon

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Question

• What type of processes require validation?
• Do these processes require validation?
• Bonding
• Cutting
• Dipping
• Test Methods
• Cleaning
• Assembly

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Process Changes

• When do changes to a process require
  re-validation?
• Changes to the process could impact or influence
  the device
• Specifications
• Performance
• Functionality
• Chemical Properties
• Physical Properties

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FDA-483 Trends

• Process Validation Observations 352

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Process Validation Observations

• 21 CFR 820.75(a) 175
• General
• A process whose results cannot be fully verified
  by subsequent inspection and test has not been
  adequately fully validated and approved
  according to established procedures

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Process Validation Observations

• 21 CFR 820.75(a) 88
• Documentation - general
• Process validation activities and results have
  not been fully documented

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Process Validation Observations

• 21 CFR 820.75(b) 40
• Monitoring and control
• Procedures were not established defined
  documented complete implemented for
  monitoring and control of process parameters for
  validated processes

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Process Validation Observations

• 21 CFR 820.75(b)(2) 16
• Documentation of validated process performance
• There is no documentation of monitoring and
  control methods and data the major equipment
  used for a validated process

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Process Validation Observations

• 21 CFR 820.75(c) 13
• Documentation review in response to changes
• There is no documentation of the review and
  evaluation of a process revalidation of a
  process conducted in response to changes or
  process deviations

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Process Validation Observations

• 21 CFR 820.75(c) 11
• Process changes review, evaluation and
  revalidation
• A validated process was not reviewed and
  evaluated revalidated when changes or process
  deviations occurred

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Process Validation Observations

• 21 CFR 820.75(a) 6
• Documentation specific items
• Documentation of process validation activities
  and results does not include the date and
  signature of the individuals approving the
  validation the major equipment validated

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Process Validation Observations

• 21 CFR 820.75(b)(1) 3
• Performed by qualified individual
• A validated process was not performed by a
  qualified individual

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Process Validation Observations

• 21 CFR 820.70(b) 120
• Changes to a specification method process
  procedure were not verified or validated
• Procedures for changes to specification
  methods processes were not established
  defined documented complete implemented
• Established procedures were not followed in
  making changes to specifications methods
  processes procedures
• Changes were not documented followed

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Process Validation

• Case Study Inspection of a Packaging Process

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Packaging Process Validation

• The package of a sterile medical device serves to
  protect the product and maintain sterility of the
  product until the package is opened by the user
• Why validate the packaging process?
• Maintain package integrity
• Assure the integrity of the seal
• Maintain microbial barrier

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Inspection Process

• The packaging materials ability to be sterilized
  and maintain its sterility is determined by
• Material selection
• Package design
• Process development
• Procedures
• Packaging process validation
• Package testing

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Inspection Process

• Indicators from other subsystems may guide the
  investigator to cover the packaging process under
  the PPC subsystem.

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Management Controls Subsystem

• Management controls over the sterile device
  packaging development and operations
• Quality audits
• Employee training
• Adequate resources
• Knowledge of the nature of the product/package
  and its limitations during sterilization,
  handling, and storage
• Quality System Procedures

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Design Control Subsystem

• Materials selected must
• Compatible with the product, manufacturing
  method, and sterilization method
• Maintain product sterility until time of use
• Provide product protection
• Consider biocompatibility for the intended use

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Package Materials and Design

• Requirements to consider
• Permeability
• Microbial barrier properties
• Formation of toxins during processing
• Interaction between products and package
  materials
• Chemical properties pH value, chloride and
  sulfate content
• Labeling of package

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Package Materials Design

• Requirements to consider
• Physical properties tensile strength, thickness
  variation, tear variation, burst strength
• Adhesive, coated materials coating patterns,
  minimum specified seal strength

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Design Control Subsystem

• Design control requirements for the development
  of physical specifications of the packaging
  materials
• Physical requirements
• Dimensions
• Tolerances
• Description of raw materials, components
• Thickness
• Coatings required
• Graphic treatment
• Colors, type of ink, type of printing process

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Design Control Subsystem

• Design control requirements for the development
  of performance specifications of the packaging
  materials
• Performance requirements
• Porosity
• Bursting strength
• Seal strength
• Peel strength
• Tensile and elongation properties
• Permeability to gases and moisture

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Corrective Preventive Actions (CAPA) Indicators

• Complaints
• Open packages
• Poor seal
• Tears
• Loss of sterility
• Infections
• Foreign objects

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CAPA Indicators

• Medical Device Reports
• Toxins formed during processing
• Infections
• Recalls-Packaging Problems/Loss of Sterility
• Holes in packaging
• Unknown/unspecified packaging complaints
• Seams or seals
• Design or process
• Packaging/labeling mix-ups

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CAPA Indicators

• Returned Goods Authorization
• Open package
• Poor seals
• Tears
• Non-conformances
• In-process failures
• Receiving inspection non-conformances
• Finished testing non-conformances

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Inspection Process - PPC

• Review the procedures
• Methods for controlling and monitoring the
  packaging process
• Review device history records
• Non-conformances
• Review of process or material changes
• Training records

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Inspection Process

• Purchasing controls
• Supplier evaluation and approval
• Material specifications/changes
• Packaging process validation
• Installation Qualification
• Operational Qualification
• Performance Qualification

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Validation Deficiencies

• Lack of operational qualification data to support
  the parameters/ranges used in the process
• Failure to define the process parameters prior to
  the performance of the qualification runs
• Sampling sizes not based on statistical rationale

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Validation Deficiencies

• Failure to demonstrate consistent results over
  time through successful runs
• Failure to validate test methods
• Failure to perform shipping or environmental
  stress testing
• Failure to include product in package seal
  testing
• Lack of data to demonstrate reproducibility

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Packaging Process Deficiencies

• Lack of written procedures for the inspection of
  incoming packaging materials
• Failure to establish sealing parameters
• Failure to perform finished product seal
  integrity testing
• Samples collected for testing are not
  representative of the packaging run

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Packaging Process Deficiencies

• Failure to document results and maintain records
  of the packaging inspections
• Failure to maintain and/or calibrate equipment
• Failure to monitor the temperature, pressure, and
  dwell time for the heat sealers

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Packaging Process Deficiencies

• Lack of a supplier evaluation/qualification
• Failure to monitor or control the product
  received from suppliers
• Failure to establish or reference the specified
  requirements

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Questions